Abstract Fragile X syndrome (FXS) is the most common inherited cause of mental retardation (MR), and unintelligible speech is a very common characteristic of young males with FXS. The proposed competing continuation study will compare segmental and prosody/voice features and speech intelligibility and identify potential mechanisms underlying individual differences in speech intelligibility of boys with FXS, Down syndrome (DS), and typical development (TD) to determine whether individual differences in speech production relate to FXS specifically or to MR in general. The specific aims of this study are to: a) identify syndrome-specific differences in speech characteristics (segmental, prosody/voice, and intelligibility) in FXS or DS; b) determine how segmental and prosody/voice features relate to lower levels of speech intelligibility in boys with FXS and test whether the predictors of intelligibility differ among boys with FXS, DS, and TD; and c) identify potential mechanisms (anxiety/arousal, motor speech, nonverbal cognition, attention) that may account for anticipated group differences in speech intelligibility among boys with FXS and DS. Sixty-five boys with FXS, 40 boys with DS, and 80 TD boys (30 with similar mental age [TD-MA] and 50 with similar chronological age [TD-CA]) will participate in the study. The boys with FXS, DS, and the TD-CA boys will be between 8 and 12 years of age and the TD-MA boys will be between 4 and 6 years of age. All groups except the TD-CA will have nonverbal MAs between 4 and 6 years. Speech production in single words, imitated sentences, and conversational speech will be examined for temporal (contrast duration, VOT) and spectral (vowel space, F2 interquartile range) segmental features, prosody/voice features (actual rate, fundamental frequency [F0 ] levels and variability, final intonation contour), and speech intelligibility (perceived intelligibility, words intelligible). Direct magnitude estimatIion (DME) studies will be used to examine perceived intelligibility. We will examine the motor speech (oral motor function), cognition (nonverbal cognition, attention), and adaptive behavior (anxiety/arousal) of boys with FXS, DS, and TD-MA annually for three consecutive years. TD-CA boys will be assessed twice (every other year). Fragile X Mental Retardation Protein (FMRP) analysis will also be done on blood samples from the boys with FXS. Growth curve methods will contrast patterns of change over time in the overall level and rate of growth in speech development for the three groups of boys to identify syndrome- specific differences in speech characteristics, determine predictors of intelligibility and ascertain if they are syndrome-specific, and test hypothesized mediators of group differences in speech intelligibility. The ability to be understood is critical for effective communication, and poor speech intelligibility compromises all aspects of communicative competence in daily interactions. Determining whether there is a specific speech phenotype for FXS that is syndrome-specific or characteristic of MR as well as determining the potential mechanisms underlying speech intelligibility difficulties has significant implications for determining treatment protocols. Project Narrative The ability to be understood is critical for effective communication and poor speech intelligibility compromises all aspects of communicative competence in daily interactions. Fragile X syndrome (FXS) is the most common inherited cause of mental retardation, and unintelligible speech is a very common characteristic of boys with FXS. Determining whether there is a specific speech profile for FXS that is syndrome specific or characteristic of mental retardation, as well as determining the potential mechanisms underlying speech intelligibility difficulties, has highly significant implications for determining treatment protocols.